Oswalt first began performing standup comedy in the late 1980s or early 1990s, by his own reckoning. After writing for MADtv and starring in his own 1996 comedy special for HBO, he went on to garner notable roles in films and television shows. His most prominent and long-running role was as Spence Olchin on The King of Queens. His first starring film role was as the voice of Remy, the lead character in the 2007 Pixar film Ratatouille. He has also appeared in smaller roles in such films as Magnolia and Madagascar: Escape 2 Africa. He lent his voice as in the video game Grand Theft Auto: San Andreas as a caller on the WTCR show "The Tight End Zone", and was the voice of a caller on "Chatterbox" on LCFR in the game Grand Theft Auto: Liberty City Stories. He was also the voice of a reporter on "New World Order", a radio show on VCPR in Grand Theft Auto: Vice City Stories.
Oswalt wrote the comic book story "JLA: Welcome to the Working Week", a backup story in Batman #600; a story for Dwight T. Albatross's The Goon Noir #01 and a story for Masks: Too Hot for TV. Expanding his voice artist repertoire, he began voicing the villainous character "Tobey" on PBS Kids GO! series WordGirl in 2007. He also appeared on the Comedy Central Roast of William Shatner. In August 2007, he appeared on the Comedy Central Roast of Flavor Flav. In 2007, he appeared on an episode of SpongeBob SquarePants, "The Original Fry Cook", as Jim. He also appears as Carl, the Corndog Hut's mascot in American Hi-Fi's music video for "Another Perfect Day". He also appears in an episode of Static Shock. On June 27, 2007, Oswalt was a special guest on the Emeril Live program on the Food Network to promote Ratatouille. Other recent appearances include an episode of Venture Bros. where he voiced an aging boy adventurer Robin parody. In 2008 Oswalt moderated a reunion panel of the Mystery Science Theater 3000 cast at the San Diego Comic-Con International.
In 2009, Oswalt played Paul Aufiero, the leading role in Robert D. Siegel's 2009 directorial debut, Big Fan. He was to star in a 2010 Broadway revival of Lips Together, Teeth Apart. However, the show was postponed then eventually canceled due to Megan Mullally's departure from the production when the director denied her request to replace Oswalt due to his lack of stage experience.
He starred in the Showtime drama The United States of Tara as Neil, an employee of Four Winds Landscaping. He also provides the voice of Thrasher, a robot protagonist from the new Cartoon Network show, Robotomy.
In January 2011, Oswalt released his first book, Zombie Spaceship Wasteland.
In November 2011, Oswalt played the role of Hurlan Heartshe in the surrealist comedy miniseries The Heart, She Holler on Cartoon Network's late-night programming block, Adult Swim. In 2011, Oswalt also played the role of Matt Freehauf in Jason Reitman's black comedy Young Adult.